An enantiomer is one of two stereoisomers that are not superimposable mirror images of each other, much as one's left and right hands are mirror images but are not superimposable. Enantiomers have essentially identical physical (except for their ability to rotate plane-polarized light by equal amounts but in opposite directions) and chemical (except in a chiral environment) properties. A mixture of equal parts of an optically active isomer and its enantiomer is a racemate, and has a net rotation of plane-polarized light of zero.
Many drug molecules are chiral, and synthetic chemical reactions involved in their production often produce racemates. However, since many biomolecules are chiral, there may be a marked difference in the effects of the two enantiomers in a racemate on living beings, including human beings. Differences in biologic effects, if any, between enantiomers in a racemate or between separate enantiomers and their racemate combination, is extremely difficult to predict a priori, and may include no differences, different pharmacokinetics, and quantitatively or qualitatively different pharmacologic or toxicologic effects.
For example, cases in which both enantiomers in a racemate had similar biologic activity include: both enantiomers of dobutamine which are positive inotropes; both ibuprofen enantiomers which are anti-inflammatory agents; both enantiomers of warfarin and phenprocoumon which are anticoagulants; and the enantiomers of bupivicaine which both produce local anesthesia.
Alternatively, cases in which one enantiomer in a racemate had biologic activity and the other had no activity include: the enantiomers of the quinolones (e.g., 1-propranolol is a (3-blocker and d-propranolol is not) and the β-lactam antibiotics.
In still other examples, cases in which each enantiomer in a racemate had completely different activities include racemic sotalol, where d-sotalol is a type 3 antiarrhythmic agent and 1-sotalol is a β-blocker. In these cases, there are even instances in which toxicity has been linked to the enantiomer not responsible for the desirable activity of the racemate. For example, granulocytopenia is related to the d-isomer of levodopa; vomiting is caused by the d-isomer of levamisole; and myasthenia gravis symptoms were no longer observed when the d-isomer was removed from racemic carnitine.
Due to the potential for the enantiomers in a racemate to have different pharmacological effects on living beings, it is generally desirable to develop a drug manufacturing process that produces substantially only a single enantiomer. A disadvantage of this approach is the higher cost associated with a process that produces substantially a single enantiomer as compared to a process that produces the racemate.
Whereas choosing to develop a drug as a racemate may reduce the post-approval manufacturing costs relative to producing one of its enantiomers in substantially pure form, this is countered in the pre-approval phase by the higher costs associated with the increased regulatory burden of developing the racemate. The increased regulatory burden of the racemate arises from additional testing and development requirements in manufacturing control, pharmacologic and toxicologic assessment, characterization of metabolism and distribution, and clinical evaluation.
“Aminopterin [54-62-6]N-[4-[[(2,4-Diamino-6-pterdinyl)methyl]amino]benzoyl]-L-glutamic acid” (page 83, The Merck Index, 13th Edition, Merck & Co., Inc., Whitehouse Station, N.J. 2001) is described and used in the art as the L enantiomer. According to The Merck Index, aminopterin is prepared “from 2,4,5,6-tetraminopyrimidine sulfate, 2,3-dibromopropionaldehyde and p-aminobenzoylglutamic acid: Seeger et al., J. Am. Chem. Soc. 69, 2567 (1947); from 6-(bromomethyl)-2,4-diaminopteridine HBr: Piper, Montgomery, J. Heterocycl. Chem. 11, 279 (1974).” Therefore, the use of the term “aminopterin” in the art refers to the L enantiomer.
It would therefore be a significant advantage if a drug could be developed as its racemate, while obviating many of the additional testing and development costs relative to developing it as a single enantiomer. It would be a further advantage if the racemate (i.e., the combination of the enantiomers) had additional favorable biologic properties compared to the enantiomer responsible for the majority of the desired biologic effects. Aminopterin, or N-4-[[2,4-diamino-6-pteridinyl)-methyl]amino]benzoy-1]-L-glutamic acid, is a potent antifolate useful for treating a variety of human and animal diseases. It is optically active, having a single chiral center.